Bile acid toxicity structure–activity relationships: Correlations between cell viability and lipophilicity in a panel of new and known bile acids using an oesophageal cell line (HET-1A)

2010 ◽  
Vol 18 (18) ◽  
pp. 6886-6895 ◽  
Author(s):  
Ruchika Sharma ◽  
Ferenc Majer ◽  
Vijaya Kumar Peta ◽  
Jun Wang ◽  
Ray Keaveney ◽  
...  
Keyword(s):  
Bile Acid ◽  
Cell Viability ◽  
Bile Acids ◽  
Cell Line ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
Acid Toxicity

scholarly journals Recent advances in understanding bile acid homeostasis

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 2029 ◽  
Author(s):  
John YL Chiang
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Farnesoid X Receptor ◽  
Recent Advances ◽  
Bile Acid Pool Size ◽  
Bile Acid Receptor ◽  
Acid Toxicity ◽  
G Protein Coupled

Bile acids are derived from cholesterol to facilitate intestinal nutrient absorption and biliary secretion of cholesterol. Recent studies have identified bile acids as signaling molecules that activate nuclear farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, also known as TGR5) to maintain metabolic homeostasis and protect liver and other tissues and cells from bile acid toxicity. Bile acid homeostasis is regulated by a complex mechanism of feedback and feedforward regulation that is not completely understood. This review will cover recent advances in bile acid signaling and emerging concepts about the classic and alternative bile acid synthesis pathway, bile acid composition and bile acid pool size, and intestinal bile acid signaling and gut microbiome in regulation of bile acid homeostasis.

Structure-activity relationships in calcitonin gene-related peptide: Cyclic AMP response in a preosteoblast cell line (ks-4)

2009 ◽  
Vol 6 (10) ◽  
pp. 1137-1142 ◽  
Author(s):  
Daniel Thiebaud ◽  
Takuhiko Akatsu ◽  
Takeyoshi Yamashita ◽  
Tatsuo Suda ◽  
Toshiharu Noda ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Cell Line ◽  
Calcitonin Gene Related Peptide ◽  
Structure Activity Relationships ◽  
Related Peptide ◽  
Structure Activity ◽  
Calcitonin Gene

scholarly journals The Cholangiocyte Glycocalyx Stabilizes the ‘Biliary HCO3- Umbrella': An Integrated Line of Defense against Toxic Bile Acids

2015 ◽  
Vol 33 (3) ◽  
pp. 397-407 ◽  
Author(s):  
Lucas J. Maillette de Buy Wenniger ◽  
Simon Hohenester ◽  
Luca Maroni ◽  
Sandra J. van Vliet ◽  
Ronald P. Oude Elferink ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Protective Layer ◽  
Enzymatic Digestion ◽  
Biliary Cirrhosis ◽  
Membrane Glycoproteins ◽  
Neuraminidase Treatment ◽  
Protective Function ◽  
Membrane Bound ◽  
Acid Toxicity

Background: Destruction of cholangiocytes is the hallmark of chronic cholangiopathies such as primary biliary cirrhosis. Under physiologic conditions, cholangiocytes display a striking resistance to the high, millimolar concentrations of toxic bile salts present in bile. We recently showed that a ‘biliary HCO3- umbrella', i.e. apical cholangiocellular HCO3- secretion, prevents cholangiotoxicity of bile acids, and speculated on a role for extracellular membrane-bound glycans in the stabilization of this protective layer. This paper summarizes published and thus far unpublished evidence supporting the role of the glycocalyx in stabilizing the ‘biliary HCO3- umbrella' and thus preventing cholangiotoxicity of bile acids. Key Messages: The apical glycocalyx of a human cholangiocyte cell line and mouse liver sections were visualized by electron microscopy. FACS analysis was used to characterize the surface glycan profile of cultured human cholangiocytes. Using enzymatic digestion with neuraminidase the cholangiocyte glycocalyx was desialylated to test its protective function. Using lectin assays, we demonstrated that the main N-glycans in human and mouse cholangiocytes were sialylated biantennary structures, accompanied by high expression of the H-antigen (α1-2 fucose). Apical neuraminidase treatment induced desialylation without affecting cell viability, but lowered cholangiocellular resistance to bile acid-induced toxicity: both glycochenodeoxycholate and chenodeoxycholate (pKa ≥4), but not taurochenodeoxycholate (pKa <2), displayed cholangiotoxic effects after desialylation. A 24-hour reconstitution period allowed cholangiocytes to recover to a pretreatment bile salt susceptibility pattern. Conclusion: Experimental evidence indicates that an apical cholangiocyte glycocalyx with glycosylated mucins and other glycan-bearing membrane glycoproteins stabilizes the ‘biliary HCO3- umbrella', thus aiding in the protection of human cholangiocytes against bile acid toxicity.

scholarly journals Structure-activity relationship of bile acids and bile acid analogs in regard to FXR activation

2003 ◽  
Vol 45 (1) ◽  
pp. 132-138 ◽  
Author(s):  
Tomofumi Fujino ◽  
Mizuho Une ◽  
Tsuneo Imanaka ◽  
Kazuhide Inoue ◽  
Tomoko Nishimaki-Mogami
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Structure Activity Relationship ◽  
Activity Relationship ◽  
Structure Activity ◽  
Relationship Of

scholarly journals Pyrrolizidine Alkaloids Disturb Bile Acid Homeostasis in the Human Hepatoma Cell Line HepaRG

Foods ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 161
Author(s):  
Julia Waizenegger ◽  
Josephin Glück ◽  
Marcus Henricsson ◽  
Claudia Luckert ◽  
Albert Braeuning ◽  
...  
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Cell Line ◽  
Pyrrolizidine Alkaloids ◽  
Hepatoma Cell ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Hepatoma Cell Line ◽  
Human Hepatoma ◽  
Human Hepatoma Cell

1,2-unsaturated pyrrolizidine alkaloids (PAs) belong to a group of secondary plant metabolites. Exposure to PA-contaminated feed and food may cause severe hepatotoxicity. A pathway possibly involved in PA toxicity is the disturbance of bile acid homeostasis. Therefore, in this study, the influence of four structurally different PAs on bile acid homeostasis was investigated after single (24 h) and repeated (14 days) exposure using the human hepatoma cell line HepaRG. PAs induce a downregulation of gene expression of various hepatobiliary transporters, enzymes involved in bile acid synthesis, and conjugation, as well as several transcription regulators in HepaRG cells. This repression may lead to a progressive impairment of bile acid homeostasis, having the potential to accumulate toxic bile acids. However, a significant intracellular and extracellular decrease in bile acids was determined, pointing to an overall inhibition of bile acid synthesis and transport. In summary, our data clearly show that PAs structure-dependently impair bile acid homeostasis and secretion by inhibiting the expression of relevant genes involved in bile acid homeostasis. Furthermore, important biliary efflux mechanisms seem to be disturbed due to PA exposure. These mole-cular mechanisms may play an important role in the development of severe liver damage in PA-intoxicated humans.

scholarly journals Single-Cellular Biological Effects of Cholesterol-Catabolic Bile Acid-Based Nano/Micro Capsules as Anti-Inflammatory Cell Protective Systems

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 73
Author(s):  
Armin Mooranian ◽  
Corina Mihaela Ionescu ◽  
Daniel Walker ◽  
Melissa Jones ◽  
Susbin Raj Wagle ◽  
...  
Keyword(s):  
Bile Acid ◽  
Cell Viability ◽  
Bile Acids ◽  
Chemical Stability ◽  
Targeted Delivery ◽  
Biological Activities ◽  
Biological Effects ◽  
Cell Encapsulation ◽  
Viable Cell ◽  
Thermal And Chemical Stability

Recent studies in our laboratories have shown promising effects of bile acids in ➀ drug encapsulation for oral targeted delivery (via capsule stabilization) particularly when encapsulated with Eudragit NM30D® and ➁ viable-cell encapsulation and delivery (via supporting cell viability and biological activities, postencapsulation). Accordingly, this study aimed to investigate applications of bile acid-Eudragit NM30D® capsules in viable-cell encapsulation ready for delivery. Mouse-cloned pancreatic β-cell line was cultured and cells encapsulated using bile acid-Eudragit NM30D® capsules, and capsules’ images, viability, inflammation, and bioenergetics of encapsulated cells assessed. The capsules’ thermal and chemical stability assays were also assessed to ascertain an association between capsules’ stability and cellular biological activities. Bile acid-Eudragit NM30D® capsules showed improved cell viability (e.g., F1 < F2 & F8; p < 0.05), insulin, inflammatory profile, and bioenergetics as well as thermal and chemical stability, compared with control. These effects were formulation-dependent and suggest, overall, that changes in ratios of bile acids to Eudragit NM30D® can change the microenvironment of the capsules and subsequent cellular biological activities.

scholarly journals Polycomb Paralog Chromodomain Inhibitors Active Against Both CBX6 and CBX8

2021 ◽  
Author(s):  
Natalia Milosevich ◽  
Chelsea Wilson ◽  
Tyler Brown ◽  
Aktan Alpsoy ◽  
Sijie Wang ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Line ◽  
Tumor Cell Line ◽  
Rhabdoid Tumor ◽  
Structure Activity Relationships ◽  
Disease States ◽  
Structure Activity ◽  
Aromatic Cage ◽  
Lysine Residues ◽  
Paralog Family

Methyllysine reader proteins bind to methylated lysine residues and alter gene transcription by changing the compaction state of chromatin or by the recruitment of other multiprotein complexes. The polycomb paralog family of methyllysine readers bind to trimethylated lysine on the tail of histone 3 via a highly conserved aromatic cage located in their chromodomains. Each of the polycomb paralogs are implicated in several disease states. CBX6 and CBX8 are members of the polycomb paralog family with two structurally similar chromodomains. By exploring the structure-activity relationships of a previously reported CBX6 inhibitor we have discovered more potent and cell permeable analogs. Our current report includes potent, dual-selective inhibitors of CBX6 and CBX8. We have shown that the –2 position in our scaffold is an important residue for selectivity amongst the polycomb paralogs. Preliminary cell-based studies show that the new inhibitors impact cell proliferation in a rhabdoid tumor cell line. This report includes data on inhibitor design, inhibitor synthesis, compound characterization by LCMS, compound activity by fluorescence polarization, analysis of structure-activity relationships, rhabdoid tumor cell line activity.

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